Steroids intermediates having a 17a-hydroxy-13-hydrocarbon substituted 8,14-secogona-1,3,5(10),9,15-pentaen-14-one nucleus

ABSTRACT

A process is described for preparing a compound having a 13hydrocarbon substituted-gona-1,3,5(10),8,14-pentaen-17 Alpha -o1 nucleus from a compound having a 17 Alpha -hydroxy-13-hydrocarbon substituted-8,14-secogona-1,3,5(10),9,15-pentaen-14-one nucleus via a compound having a 13 Alpha -hydrocarbon substituted-9,14oxido-8,14-secogona-1,3,5(10),15-tetraen-17-one nucleus and a compound having a 13 Alpha -hydrocarbon substituted-9,14-oxido8,14-secogona-1,3,5(10)-trien-17-one nucleus. A process is also described for preparing the compound having the 17 Alpha hydroxy-13-hydrocarbon substituted 8,14-secogona-1,3,5(10),9,15pentaen-14-one nucleus from a 13-hydrocarbon substituted-8,14secogona-1,3,5(10),9,15-pentaene-14,17-dione by MeerweinPonndorf-Verley reduction. Novel intermediates for preparing known compounds of known utility by per se known methods are disclosed.

United States Patent Hiraga et al. [451 Sept. 5, 1972 54] STEROIDS INTERMEDIATES HAVING [56] References Cited A 17A-HYDROXY-13-HYDROCARBON I SUBSTITUTED 8,14-SECOGONA- OTHER PUBLICATIONS 1,3,5(l0),9,15-PENTAEN-l4-ONE NUCLEUS Inventors: Kentaro Hiraga, Ikeda; Tsunehiko Asako, Suita; Takuichi Miki, Amagasaki, all of Japan Assignee: Takeda Chemical Industries, Ltd.,

Osaka, Japan Filed: March 21, 1968 Appl. No.: 714,772

Foreign Application Priority Data Djerassi, Steroid Reactions, 148- 149 (1963) Primary Examiner-Daniel D. Horwitz Attorney--Wenderoth, Lind & Ponack ABSTRACT A process is described for preparing a compound having a l 3-hydrocarbon substituted-gonal,3,5(lO),8,l4-pentaen-17a-ol nucleus from a compound having a l7a-hydroxy-l3-hydrocarbon substituted-8, l 4-secogona-l ,3 ,5 10),9, l S-pentaenl 4-one nucleus via a compound having a l3a-hydrocarbon substituted-9,14-oxido-8,14-secogona-l,3 ,5( 10), l 5- tetraen-17-one nucleus and a compound having a 13ahydrocarbon l,3,5(lO)-trien-l7-one nucleus. A process is also described for preparing the compound having the 1 7a-hydroxy-1 3-hydrocarbon substituted 8, 14- secogona-l ,3,5( 10),9,l S-pentaenl 4-one from a Iii-hydrocarbon substituted-8,l4-secog0nal,3,5(10),9,l5-pentaene-l4,l7-dione by Meerwein- Ponndorf-Verley reduction. Novel intermediates for preparing known compounds of known utility by per se known methods are disclosed.

2 Claims, No Drawings substituted-9, l 4-oxido-8, l 4-secogona-.

nucleus STEROIDS INTERMEDIATES HAV ING A 17A- HYDROXY- l 3-HYDROCARBON SUBSTITUTED 8 l 4-SECOGONA- l ,3 ,5( l ),9 l S-PENTAEN-l 4-ONE NUCLEUS The present invention relates to a novel process for producing a compound having a l3-hydrocarbon substituted-gona-l,3,5(l0), 8,14-pentaen-l7a-ol nucleus, employing as the starting material a compound having a l7a-hydroxy-l3-hydrocarbon substituted-8,14- secogona-l,3,5(l0), 9,15-pentaen-l4-one nucleus, of which cyclization to form the steroidal skeleton having a natural configuration cannot be performed under such known conditions as described in Chemistry and Industry, July 30, 1966, pp. 1,340-1 ,341.

The principal object of this invention is to embody a process for producing a compound having a 13- hydrocarbon substituted-gona-l ,3 ,5( l0), 8 l 4-pentaen-17a-ol nucleus, employing as the starting material a compound having a I7a-hydroxy-l3-hydrocarbonsubstituted-8,14-secogona-l ,3 ,5( 10) ,9, l -pentaenl 4- one nucleus. Another object of this invention is to provide novel compounds having a 17a-hydroxy-l3-hydrocarbon substituted-8, l4-secogona-l ,3 ,5( l0) ,9, l S-pentaenl 4- one nucleus and novel compounds having a 13ahydrocarbon substituted-8,14-oxido-8 l 4-secogonal,3,5(), l5-tetraen- 1 7-one nucleus.

Other objects will become apparent from the detailed description hereinafter provided.

Compounds having a l7a-hydroxyl SB-hydrocarbon substituted-8,14-secogona-l ,3,5( 10) ,9, 1 S-pentaenl 4- one nucleus (IV) OH R; i

, W3 m A i used as the starting materials of the present invention, are prepared, for example, by subjecting corresponding compounds having a l3-hydrocarbon substituted-8,14- secogona-l ,3,5( l0),9,15-pentaene-l4,l7-dione nucleus (III) to Meerwein-Ponndorf-Verley reduction employing aluminum alkoxide (e.g. aluminum isopropoxide, aluminum phenoxide, etc.) in a solvent generally used for a steroidal reaction (e.g. methanol, ethanol, isopropanol, butanol, tetrahydrofuran, dioxane, ether, petroleum ether, chloroform, benzene, toluene, etc.) at a temperature of 60C to 85C, or by subjecting the same compound to a biological selective reduction employing a microorganism of the genus Kloeckera (e.g. Kloeckera magna, etc.

The above-mentioned compound having a 13- hydrocarbon substituted-8, l 4-secog0nal ,3,5( l 0 ),9,l5-pentaene-l4,l7-dione nucleus (III) is prepared by, for example, a condensation reaction between a compound having a 4-hydroxy or 4-acyloxy-2- hydrocarbon substituted-cyclopentane-l ,3-dione nucleus (I) and a compound having a l-hydroxy-lvinyl-tetra line nucleus or S-2-( 1 -tetraliden)ethylthiuronium nucleus (II) to give a compound having a 8,14- secogona-l ,3 ,5( l0),9, I S-pentaen-l 4, l 7-dione nucleus (III) optionally in the presence of a basic catalyst. The expression compound having a 4-hydr0xyor 4- acyloxy-2-substituted cyclopentane-l ,3-dione nucleus refers to a compound (I) which has the general structure represented by the formula wherein R is a hydrocarbon residue, which is exemplified by lower alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary butyl), phenyl and benzyl, and wherein R is a hydrogen atom or an acyl radical derived from a carboxylic acid e.g. acetyl, propionyl, butyryl, benzoyl, ethoxycarbonyl, etc. One of the hydrogen atoms at the position 5 of the compound (I) can further be replaced by a hydrocarbon residue as exemplified above. By compounds having the l-hydroxy-l- -vinyl-tetraline nucleus or S-2-(l'- tetralidene)ethylthiuronium nucleus are meant com-' pounds of the general structure represented by the formulas 8-0 8 OH 8 l 1 7 2 7 6 I 3 or ll 3 Rl/\5/4 R1/\5/4 wherein R is a hydrogen atom, hydroxyl, an etherified hydroxyl radical (e.g. methoxy, ethoxy, benzyloxy, etc.), or an esterified hydroxyl radical (e.g. acetyloxy, nicotinoyloxy, etc.), and wherein X is a lower acyloxy or lower alkylcarbonyloxy radical (e.g. acetyloxy, propionyloxy, etc.), a halogen ion (e.g. chloride, bromide), the perchloro radical, the sulfate radical, etc., and which compounds can be substituted, for example, at one or more of the positions 3, 4, 5, 7 and 8 in the tetrahydronaphthalene skeleton, by a hydrocarbon residue such as lower alkyl (e.g. methyl, ethyl, npropyl, isopropyl, n-butyl and isobutyl), phenyl or benzyl, and/or, at one or more of the positions 5, 7 and 8 in the skeleton, by a hydroxyl group, an etherified hydroxyl or lower alkoxy group (e.g. methoxy, ethoxy, n-propoxy and n-buto y), and esterified hydroxyl group (e.g. acetoxy, propionyloxy and benzoyloxy), a halogen atom (e.g. fluorine and chlorine), a thio group (e.g. mercapto, methylthio, ethylthio and acetylthio) and an acyl group derived from a carboxylic acid (e.g. acetyl, propionyl and benzoyl).

The thus-obtained compound having a l7a-hydroxy can be carried out at an elevated or lowered tempera- 13 -substituted-8,l4-secogona-l ,3,5( 10), 9-tetraen-l4- ture. In any event, too drastic conditions should be one nucleus (IV), the starting material of the present avoided for this reaction, since there may take place invention is exemplified as follows: hydrogenolysis at position 9. 17a-I-Iydroxy-l3B-methyl-8,l4-secogona-l,3,5(10),9- 5 The thus-obtained compound having a 13atetraen-14-one; hydrocarbon substituted-9,l4-oxido18,l4-secogonal7a-I-Iydroxy- 1 3B-methyl-3-methoxy-8, l4-secogonal ,3 ,5( )-trienl 7-one nucleus 1,3,5( 10) 9-tetraen-l4-one; O l 7a-I-Iydroxyl 3B-methyl-3-ethoxy-8, l 4-secongona- 1,3,5(10),br9-tetraen l4-one; l7a-Hydroxy-l3B-ethyl-8,l4-secogona-l ,3,5 1o ,9- tetraenl 4-one; o l7a-I-Iydroxyl 3B-isopropyl-8 14-secogonal ,3 ,5( l0 9-tetraen-14-one; 15 l7a-Hydroxy-3-methoxy-l 3B-ethyl-8,l4-secogona- I 4 (VI) l,3,S-( 10),9-tetraen-l4-one; 7 3 13 1 14 is finally brought into contact with acid catalyst to 1 3 5 0 9 14 v produce a compound having a l3a-substituted-gonal7a-Hydroxy-3-methoxy-l 3 B-isopropyl-8 ,14- 2O 1 ,3 'P nucleus secogona-l ,3 ,5( l0) ,9-tetraenl 4-one; etc. on

The first step of the present invention comprises contacting the compound having a 13B-hydrocarbon substituted-8,14-secogona-tetraen-l7B-ol nucleus (IV) with acid catalyst, whereupon intramolecular cyclization takes place to give a compound having a 13ahydrocarbon substituted-9, l 4-oxido-8 1 4-secogona- R 1,3,5 10 l5-tetraen-l7-one nucleus: (v11 R2 9,14-oxido-8, l 4 This reaction can be carried out under preparing a compound having a l3a-hydrocarbon substituted-9, l 4-secogonal ,3 ,5( l0), 1 S-tetraen- 1 7-one /YW the same conditions as employed in the process for L, l nucleus (V) from the compound having a 13a- @3 hydrocarbon substituted-8,l4-secogona-l,3,5(l0

),9,l5-pentaen-l4one l7a-ol nucleus (IV). R1 (V) The thus obtained l3B-substituted -l7a-hydrox- The acid catalyst is exemplified by inorganic acids or ygona'pemaene their anhydrides (e.g. hydrochloric acid, sulfuric acid, 40 phosphoric acid, phosphorus pentoxide and polyphosphoric acid), partial salts or partial esters of the polybasic inorganic acids (eg sodium hydrogen sulfate, monosodium dihydrogen' phosphate and monomethyl sulfate), their pyridine complexes (e.g. pyridine-hydrobromic acid complex), sulfonic acids R1 (e.g. methane-sulfonic acid, ethanesulfonic acid, benzenesulfomc and i toluenesulfom? 3 can be converted steroselectively and exclusively to the fonated styrene-type cation exchange resins, so-called corresponding 13 p substimted gona l3,5(10), Lewis acids (e.g. aluminum chloride, boron trifluoride n-$ 47, 1 and tin chloride), silica gel, etc. This reaction does not require any solvent. However, the reaction can be ef- R2 fected more smoothly in a suitable solvent such e.g. as benzene, toluene, xylene, tetrahydrofuran, dibutyl ether, methanol, ethanol and propanol. This reaction is l accelerated by heating e.g. to a temperature in the neighborhood of 100C or higher.

The thus-obtained compound having a 130:- R1 (VIII) hydrocarbon substituted 9,14-oxido-8,l4-secogonanucleus is Subjected in which the hydrogen attached to the position 14 is t par al ed t by S a at yti redlwtiofloriented to a-configuration; that is, the same configura- For this p p Raney nickel or palladium y t is tion as estro--genic steroids obtained from natural advantageously used. The reaction can be carried out sources. The 13B-substituted -l7a-hydroxy-gonain a suitable solvent which is exemplified by dioxane, tetraenes (VIII) can further be converted by reduction tetrahydrofuranfether, methanol, ethanol and acetic to produce, with a good overall yield, the l3B-subacid. The reaction usually takes place at ambient temstituted-gona-l,3,5(l0)-trien-l7a-ols (IX) and the perature (e.g. at about 15 to 30C); but, if required, it .l3B-substituted-gona-2,S( 10)-dien-l7a-ols (XI) (VII) which compounds (IX and XI) are easily converted by oxidation to l 3 B-substituted-gona-l ,3 ,5( l0)-trienl 7- respectively, both compounds having the natural hydrogen configuration at the 8, 9 and l4-positions.

The conversion of compounds (VII) to compounds (VIII) is conveniently effected by so-called catalytic reduction. For this purpose, Raney nickel or palladium catalyst is advantageously used. The reaction can be carried out in a suitable solvent which is exemplified by 1 dioxane, tetrahydrofuran, ether, methanol, ethanol and acetic acid. The reaction usually takes place at ambient temperature, but, if required, it can be carried out at an elevated or lowered temperature. If desired, more drastic conditions are employed to obtain further hydrogenated product at the positions 8 and 9, in which the hydrogen at the 8-position is in opposite configuration to that of the natural type steroids.

The reduction of compounds (VIII) to compounds (IX) is advantageously carried out by allowing an alkali metal to react with compounds (VIII) in liquid ammonia. The alkali metal may be lithium, sodium or potassium, for example. The reaction is carried out in liquid ammonia or a mixture thereof with an inert solvent, for example, ether, dioxane and tetrahydrofuran. Since reaction conditions are rather violent, the reaction is usually brought about at a lower temperature, i.e. below ambient temperature to about 30C. The reduction of compounds (IX) to compounds (XI) is advantageously carried out by allowing an alkali metal to react with the compounds (IX) in liquid ammonia containinga proton source such as an alcohol having up to six carbon atoms (e.g. methanol, ethanol, tertiary-butanol, etc.), other conditions being the same as above. In the same manner as this reaction, a compound having a 1 3-substitutedl ,3,5( l0),8-tetraen-17-ol nucleus (VIII) can also be converted to the same produce (XI), saturating the double bond at the position 8 as well as a jected to s'o-called Oppenauer oxidation employing aluminum isopropoxide, aluminum ethoxide, aluminum phenoxide, pyridine-chromic acid anhydride, etc., to oxidation employing pyridine-chromic acid anhydride or dimethylsulfoxide-dicyclohexylcarbodiimide, to oxidation employing microorganisms, etc., to produce a compound having a l3-substituted-gona-trien-l7-one nucleus (X) or to produce a compound having a 13- substituted-gona dien-17-one nucleus (XII) respectively, both having the same configuration as estrogenic steroids obtained from natural sources.

. The foregoing reactions proceed irrespective of optically active or inactive compounds employed as the starting materials. I

It is to be understood that the following exemplifications are solely for the purpose of illustration and are not to be construed as limitations of this invention, and that minor variations may be resorted to without departing from the spirit and scope of this invention. In the following, g. and ml. are gram(s) and milliliter(s), respectively. Temperatures are all uncorrected, and percentages are all on the weight basis.

EXAMPLE (i)3-Methoxyl 7a-hydroxyl 3 B-methyl-8, l 4- secogona-l ,3,5( 10) 9,15-pentaen-14-one.

To a solution of 0.5 g. of 3-methoxy-8,l4 secoestra- 1,3,5(l0),9,l5-pentaene-l4,l7-dione in 50 ml. of isopropanol, there is added 3 g. of aluminum isopropoxide. The mixture is heated at about C with agitation for one hour while gradually evaporating'off acetone (by-product) and isopropanol (solvent). The reaction mixture is added to an aqueous solution of Rochelle salt (sodium potassium tartrate) and the mixture is extracted with ether. The ether layer is washed with water and dried, followed by evaporation of the ether to give 0.5 g. of crystals, which are recrystallized from methanol to obtain 0.35 g. of 3-methoxy-l7ahydroxy-S, l 4-secoestra-l ,3 ,5( l0 ,9, l S-pentaenl 4- one melting at 114.5 to C. Elementary analysis: I

Calculated for C I-1 0 C, 76.48; H, 7.43

Found C, 76.57; H, 7.51

Infrared absorption:

Nuiol mag Ultraviolet absorption:

Aathnnol mp. (Q1265 (17,800)

2 (:t) 3-Methoxy-13a-methyl-9,l4-oxido-8,14-

secogona-l ,3 ,5 l),15-tetraen-17-one.

l4-one in ml. of dried benzene is added 1 m1. of 5 saturated benzene solution of para-toluenesulfonic acid and the mixture is stirred for one hour at room temperature (about to about 50C). The reaction solution is poured into water and the mixture is extracted with ether. The ether layer is washed with a 5 percent aqueous solution of sodium hydrogencarbonate and water. After being dried, the washed ether layer-is subjected to evaporation of the ether, and the residue is subjected to column chromatography on silica gel em ploying a mixed solvent of benzene and ethyl acetate (19:1 to give 0.18 g. of (i)3-methoxy-l3a-methyl- 9, 14-oxido-8, l4-secogona-l ,3,5( 10), 1 5-tetraen-17- one as oily substance.

Infrared absorption:

No absorption of hydroxyl radical is observed. Ultraviolet absorption:

(3) (i)3-Methoxy-l3a-methyl-9,14oxid0-8 ,14- secogona-1,3,5( 10)-trien- 1 7-one.

A solution of 0.15 g. of (i)3-rnethoxy-l3a-methyl- 9,14-oxido-8,l4-secogona-1,3,5(10),15-tetraen-17- one in ml. of ethanol is shaken in hydrogen gas stream in the presence of 0.08 g. of Raney nickel until about 20 ml. of hydrogen gas 'is absorbed. The catalyst is filtered off from the reaction mixture and the filtrate is condensed to obtain 0.14 g. of (i)3-rnethoxy-13a-' methyl-9,14-oxido-8 ,14-secogona-1,3 ,5( 10 )-trien- 1 7- one as oily substance.

Infrared absorption:

r gid l; 1735, 16Q8, 1498.

(4) (i)3-methoxy-l 3B-methylgona-1,3,5( 10),8,14- pentaen-17a-ol.

To a solution of 0.14, g. of (i)3-methoxy-13amethyl-9,14-oxido-8 ,l4-secogona-1 ,3 ,5( 10)-trien- 1 7- one in 10 ml. of methanol, there is added 5 ml. of con centrated hydrochloric acid. The mixture is refluxed for a while. The reaction mixture is poured into water, and the resulting mixture is extracted with ether. The ether layer is washed with an aqueous solution of sodium hydrogencarbonate and with water, followed by evaporating off the solvents to obtain 0.12 g. of (i)3- methoxy-13B-methylgona-l,3,5( l0),8,l4-pentaen-17a -ol melting at 98 to 101C, which is identified with an authentic sample by mixed melting point examination and other chemical and physical test. V

In analogous manner, any of the other here'inmentioned starting materials can beconverted into objective compounds in accordance with the following reaction chart:

o ll RT-O-om o: I

(I) (III) on o R: Re IR w 5 .J J

(IV) v) on on B2 R2 W l R1-- R1 VII (VIII) on I 0 R2 1 R2 R gg B g I (IX) (X) 3,689,564 9 10 Having thus disclosed the invention, we claim: 2. A compound according to claim 1, namely, 3- l. The compound 3-lower alkoxy-l7a-hydroxy-13B- M h Xy-l7a-hydr0Xy-13B-methyl-8,l4-secogonalower alkyl-8,l4-secogona-1,3,5(lQ),9,l5-pentaen-l4- l,3,5,(l0),9,15-pentaen-l4-one.

one. 

2. A compound according to claim 1, namely, 3-Methoxy-17 Alpha -hydroxy-13 Beta -methyl-8,14-secogona-1,3,5,(10),9,15-pentaen-14-one. 